NIDA-Funded Studies Shed Light on Neurobiology of Drug Craving

By Michael Muller, NIDA NOTES Staff Writer

How do environmental cues trigger drug craving in a recovering drug abuser? Is it possible to block the effects of those cues? These are key questions faced by clinicians and researchers wrestling with the problem of relapse to drug use. The answers may lie within the extended amygdala, a neural circuit that connects several structures in the lower front of the brain.

"We've known for some time that elements of the environment become tied to drug use and prompt drug craving," says Dr. Roger Brown of NIDA's Division of Basic Research. "Now, NIDA-supported investigations of the extended amygdala are telling us how this happens. They're a new and exciting approach to the issue of relapse, and this information may be important for treatment compliance."

The work of Dr. Athina Markou and Dr. George Koob at Scripps
Research Institute is helping to explain why drug abusers relapse
and how to keep them from relapsing.

The extended amygdala is part of the limbic system - a seat of memories and emotions - and is connected to other brain systems as well. "We believe that it is in the extended amygdala that memories relating to drug abuse are transformed into craving to use a drug again," says Dr. George Koob, director of the Division of Psycho-pharmacology in the Department of Neuropharmacology at the Scripps Research Institute in La Jolla, California.

How do memories give rise to craving? "Imagine a drug user who usually buys cocaine at a particular subway stop and typically experiences a drug effect shortly after the purchase," says Dr. Koob. "Eventually, the subway stop - normally a neutral part of the environment - becomes linked in the mind of the drug user to the positive rewarding effects of cocaine." Later, even after successful treatment for drug abuse, the sight of the subway stop can bring on craving for cocaine. That is, the subway stop has become a conditioned stimulus that may trigger relapse.

"Basically, we are investigating the extended amygdala and adjoining structures to figure out why drug abusers relapse and how to keep them from relapsing," says Dr. Koob. "These studies are giving rise to a better understanding of the neuro-circuitry of craving, which is getting us closer to our goal." Chronic drug use and conditioning may bring about changes that can be detected by brain scans, and these changes might be reversible through medication, psychotherapy, or both, he says.

Dr. Koob and his colleagues began their investigations of the extended amygdala by first determining whether it plays a role in the effects of drugs. Those investigations built on research by Dr. David C.S. Roberts, currently of Carleton University in Ottawa, and others. The research took two approaches.

In the first approach, the researchers inactivated the dopamine component in areas of the extended amygdala in rats after training them to self-administer cocaine. These rats significantly reduced the amount of cocaine they gave themselves. Dopamine is a chemical messenger associated with pleasure and movement. Cocaine prevents the brain cells that release dopamine from collecting it again. The resulting high levels of dopamine overstimulate the dopamine receptors - the molecules to which dopamine binds - causing the cocaine "high." This process accounts for cocaine's addictive effects, scientists believe.

Inactivation of the dopamine component of the extended amygdala reduced the rewarding effects of cocaine, an indication that the extended amygdala may be important in processing information about the rewarding effects of the drug.

In the second approach, Dr. Koob and his colleagues studied the effects on cocaine self-administration in rats when dopamine receptors in various areas of the extended amygdala were blocked by cocaine. The investigators found that the rats compensated by giving themselves larger amounts of cocaine. This research provides further evidence of a role for the extended amygdala in the rewarding effects of the drug.

"This basic neuroscience research showed us that the structures believed to form the extended amygdala not only resemble each other in design but may have similar functions," explains Dr. Athina Markou, Dr. Koob's colleague at Scripps.

Now, the Scripps investigators are pursuing lines of investigation to determine if the extended amygdala also plays a role in linking environmental stimuli to both the rewarding effects of drugs and to withdrawal.

In a series of collaborative studies with Dr. Barry Everitt from Cambridge University in England, the Scripps investigators have begun to examine the role of the basolateral nucleus (BLA) of the amygdala - a small adjoining brain structure that sends information to the extended amygdala - in conditioned drug effects, those triggered by environmental cues. In a study currently in progress, rats are exposed to light and sound cues during withdrawal from morphine. Later, when presented with the light and sound cues only, rats with inactivated BLAs are significantly less likely than rats whose BLAs are not altered to experience withdrawal. In other words, the BLA seems to play an important role in linking environmental cues to withdrawal.

In recent years, Dr. Everitt, Dr. Trevor Robbins, and other researchers at Cambridge University have found that inactivation of the BLA in rats disrupts the association of environmental stimuli with the rewarding effects of food, water, and sex. Today, Dr. Markou, in collaboration with the Cambridge researchers and with the support of a NIDA Career Development Award, is developing an animal model based on the design of the British studies for studying whether the BLA plays the same role with drugs.

Dr. Markou and colleagues have found that inactivation of the BLA interrupts the association between light and the rewarding effects of cocaine. Thus, the BLA appears to link environmental stimuli not only to withdrawal, but also to the positive effects of drugs.

"Our research is still in the early stages," Dr. Markou says. "First, we have to develop a model that allows us to study the formation of these associations. Then, we will continue to investigate the neurobiology and psychopharmacology underlying these associations and the effects of these associations on motivated behaviors."

"These findings are very exciting because they help us understand relapse behavior," says Dr. Koob. "What we're learning about the extended amygdala and its connecting structures is allowing us for the first time to identify the neurocircuits involved in conditioning processes." "We're working from the perspective of drug abuse, but the results apply to a wide range of compulsive behaviors that disrupt and destroy a great many lives each year," says NIDA's Dr. Brown. The research may help explain the neurobiological mechanisms and brain changes associated with compulsive overeating, alcohol abuse, drug addiction, smoking, compulsive gambling, and other behaviors driven by reward, withdrawal effects, and elements in the environment, he says. "This research also focuses on learning and memory," he says. "There are relatively few people working in this area of drug abuse research."

Sources

Alheid, G.F., and Heimer, L. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of the substantia innominata. Neuroscience 27:1-39, 1991.

Whitelaw, R.B.; Markou, A.; Robbins, T.W.; and Everitt, B.J. Self-administration of intravenous cocaine under a second-order schedule of reinforcement: Effects of lesions of the basolateral amygdala. Abstract presented at the Annual Meeting of the Society for Neuroscience, San Diego, CA, 1995.